可溶性Aβ42寡聚体对膜破坏作用的分子模拟研究

Soluable Aβ42 oligomers, a type of toxic aggreaged forms of Aβ42, play a causal role in Alzheimer's disease (AD)，which is directly related to the memory impairment of patients in early stage of AD. Many studies have shown the toxicity of soluble Aβ42 oligomers comes from the damage effect on plasma membrane, particularly neural cell membranes. In addition, in vivo and in vitro studies have also suggested the relation between the structure of Aβ42 oligomers and their toxicity. However, it is still unknown how the Aβ42 oligoers disrupt the plasma membrane and what structures of Aβ42 oligoers have the potential damage effect on membrane. Thus this research attempts to study, at the atomic level, the process and the possible mechanism of disrupting membrane by Aβ42 oligoerms. In this study, Temperature Enhanced Essential dynamics Replica EXchange (TEE-REX), a searching method combined Replica Exchange Molecular Dynamics (REMD) with Essential Dynamics, is used to idntify the strucutres of four small Aβ42 oligomers embedded into the membane with the explicit water model TIP3P and POPC membrane model. Subsequently, the resulting structures of these Aβ42 oligomers are used as the initial strucures of complex system composed of Aβ42 oligomer, TIP3P waters and POPC molecules. The long molecular dynamics simulations will be performed respectively for different Aβ42 oligomer systems. Based on the result of simulation,the structure and morphology of membrane as well as the structures of Aβ42 oligomer are analyzed and compared with each other to understand the reason for different strength of impact on membrane by the Aβ42 oligomers with different structures and to select the structures that have the potential damage to membrane. Therefore this study will provide the valuable insight into the mechanism of Alheimer's disease and the drug design based on Aβ42 oligomer's strucure.

可溶性Aβ42寡聚体是阿尔茨海默病早期的主要毒性物质，能引起患者在疾病初期出现记忆障碍。实验表明Aβ42寡聚体的毒性主要源自对细胞膜的破坏，同时实验证实Aβ42寡聚体结构与其毒性之间紧密相关。但目前关于Aβ42寡聚体如何破坏细胞膜以及Aβ42寡聚体形成什么结构对于细胞膜具有破坏作用尚不完全清楚。为了从原子水平上研究Aβ42寡聚体破坏细胞膜的过程，探讨Aβ42寡聚体破坏细胞膜的机制，本项目运用副本交换主成份动力学模拟方法在显式水溶液和POPC膜中对四种可溶性Aβ42寡聚体的结构进行分析，得到Aβ42寡聚体在膜中可能形成的结构，并运用分子动力学方法研究Aβ42寡聚体对膜的破坏作用。通过分析膜结构、形态改变和寡聚体结构变化，阐明不同结构寡聚体对膜发生不同程度破坏的潜在原因,筛选对细胞膜具有破坏作用的寡聚体结构，从而为进一步揭示阿尔茨海默病的发病机制和发展基于寡聚体结构的药物分子设计提供理论依据。

阿尔茨海默氏病是以记忆受损、认知和执行功能障碍为特征的一类不可逆转的渐进性、神经退行性病变。越来越多证据表明由Aβ42多肽形成的寡聚体对于神经细胞膜的破坏，引起神经细胞发生坏死是导致阿尔茨海默氏病的真正原因。因此针对Aβ42寡聚体结构和对细胞膜破坏作用的研究，对于深入了解Aβ42寡聚体在阿尔茨海默氏病发病中的作用以及有效降低Aβ42寡聚体对于细胞膜的毒性作用具有重要意义。本项目运用分子动力学模拟方法对Aβ42寡聚体中最小聚合单位（Aβ42二聚体）在DPPC膜中存在的结构和对于DPPC膜的破坏作用进行分析，研究两个Aβ42单体以不同聚合方式形成的二聚体之间的结构差别和对于DPPC膜破坏作用的差别。同时运用分子动力学模拟方法研究不同聚合状态Aβ42寡聚体，包括单体、二聚体、三聚体、四聚体和六聚体，在DPPC膜中的结构和对于DPPC膜的破坏作用。依据不同聚合形式Aβ42二聚体分子的研究,明确Aβ42多肽分子之间的聚合方式，即Aβ42二聚体的四级结构，可以通过改变Aβ42多肽链之间的氢键形成方式而影响Aβ42多肽链上“N端极性区”β折叠结构的稳定性。由于“N端极性区”β折叠结构的存在对于Aβ42多肽分子的进一步聚合以及对于DPPC膜完整性的破坏具有重要作用，因此认为在四种Aβ42二聚体中，以2NCb聚合方式形成的Aβ42二聚体是最有可能进一步聚合形成寡聚体的聚合单位，同时对于DPPC膜也具有最大程度破坏作用；通过对以相同聚合形式但不同聚合程度Aβ42寡聚体分子在DPPC膜中结构的研究，明确Aβ42多肽分子之间的聚合可以稳定Aβ42多肽分子的结构，降低Aβ42多肽分子在DPPC磷脂膜中的结构波动。同时不同聚合程度Aβ42寡聚体分子插入DPPC膜也导致膜结构的完整性发生改变，其中以Aβ42二聚体对于DPPC膜结构完整性的破坏最大。本项目取得的研究成果为设计、筛选用于抑制Aβ42寡聚体毒性作用、治疗阿尔茨海默氏病的药物分子提供了准确的药物靶标信息，具有重要的价值。